Myocardial infarction triggers chronic cardiac autoimmunity in type 1 diabetes.
Myocardial infarction triggers chronic cardiac autoimmunity in type 1 diabetes.
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DOI：
10.1126/scitranslmed.3003551
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发表时间：
2012-06-13
影响因子：
17.1
通讯作者：
Lipes MA
中科院分区：
文献类型：
--
作者：
Gottumukkala RV;Lv H;Cornivelli L;Wagers AJ;Kwong RY;Bronson R;Stewart GC;Schulze PC;Chutkow W;Wolpert HA;Lee RT;Lipes MA
1型糖尿病（T1 D）患者在心肌梗死（MI）后的发病率和死亡率过高，糖尿病的代谢作用不能完全解释这一点。已知急性MI会引发严重的先天性炎症反应，单核细胞流入并产生对心脏修复至关重要的促炎细胞因子。我们假设，这些相同的途径可能发挥“佐剂效应”，并诱导自身免疫易感T1 D宿主的病理反应。在此，我们发现非肥胖型糖尿病（NOD）小鼠的实验性心肌梗死（而非对照组C57 BL/6小鼠）导致严重的梗死后自身免疫（PIA）综合征，其特征为心肌中破坏性淋巴细胞浸润、梗死扩大、持续的心脏IgG自身抗体产生和Th 1效应细胞对心脏（α-）肌球蛋白的反应。通过诱导对α-肌球蛋白的耐受性来预防PIA，表明这种疾病过程需要对心肌肌球蛋白的免疫应答。将这些发现扩展到人类，我们开发了一组用于心脏自身抗体检测的免疫测定法，并发现83%的MI后T1 D患者的自身抗体呈阳性。我们进一步确定了心肌梗死后T1 D患者和非糖尿病心肌炎患者之间共有的心肌肌球蛋白自身抗体特征-这在心肌梗死后2型糖尿病患者中不存在-并通过心脏磁共振成像技术证实了T1 D中心肌炎的存在。这些数据为T1 D患者中独特的MI后自身免疫综合征提供了实验和临床证据。我们的研究结果表明，PIA可能导致T1 D心肌梗死后结局恶化，并强调了抗原特异性免疫干预选择性阻断这一途径的作用。
Patients with type 1 diabetes (T1D) suffer excessive morbidity and mortality following myocardial infarction (MI) that is not fully explained by the metabolic effects of diabetes. Acute MI is known to trigger a profound innate inflammatory response with influx of mononuclear cells and production of proinflammatory cytokines that are crucial for cardiac repair. We hypothesized that these same pathways might exert ‘adjuvant effects’ and induce pathological responses in autoimmune-prone T1D hosts. Here we show that experimental MI in nonobese diabetic (NOD) mice - but not in control C57BL/6 mice - results in a severe post-infarction autoimmune (PIA) syndrome characterized by destructive lymphocytic infiltrates in the myocardium, infarct expansion, sustained cardiac IgG autoantibody production and Th1 effector cell responses against cardiac (α-)myosin. PIA was prevented by inducing tolerance to α-myosin, demonstrating that immune responses to cardiac myosin are required for this disease process. Extending these findings to humans, we developed a panel of immunoassays for cardiac autoantibody detection and found autoantibody positivity in 83% post-MI T1D patients. We further identified shared cardiac myosin autoantibody signatures between post-MI T1D patients and non-diabetic patients with myocarditis – that were absent in post-MI type 2 diabetic patients - and confirmed the presence of myocarditis in T1D by cardiac magnetic resonance imaging techniques. These data provide experimental and clinical evidence for a distinct post-MI autoimmune syndrome in T1D. Our findings suggest that PIA may contribute to worsened post-MI outcomes in T1D, and highlight a role for antigen-specific immunointervention to selectively block this pathway.